Department of Orthopedics, The Second Xiangya Hospital, Central South University, 139# Middle Renmin Road, Changsha, 410013, Hunan, People's Republic of China.
Department of The Emergency, The Fourth People's Hospital of Zigong, Zigong, 643000, Sichuan, China.
Eur J Med Res. 2023 Oct 17;28(1):438. doi: 10.1186/s40001-023-01383-1.
RING finger protein 43 (RNF43), an E3 ubiquitin ligase, is a homologous gene mutated in several cancers. However, the pan-cancer panoramic picture of RNF43 and its predictive value for tumor immune phenotypes and immunotherapeutic efficacy are still largely unclear. Our study aims to clarify the functions of RNF43 in predicting the prognosis, immune signature, and immunotherapeutic efficacy in pan-cancer.
By using RNA-seq, mutation, and clinical data from the TCGA database, the expression levels and prognostic significance of RNF43 in pan-cancer were analyzed. The genetic alteration characteristics of RNF43 were displayed by the cBioPortal database. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential biological functions and signaling pathways modulated by RNF43 in cancers. The relationship of RNF43 expression with immune cell infiltration, and immune modulators expression was interpreted by the ESTIMATE algorithm, CIBERSORT algorithm, and TISIDB database. The correlations between RNF43, microsatellite instability (MSI), and tumor mutation burden (TMB) were also investigated. Furthermore, the predictive value of RNF43 for immunotherapeutic efficacy and drug sensitivity was further illustrated. Besides, immunohistochemistry (IHC) was employed to validate the expression of the RNF43 in different cancer types by our clinical cohorts, including patients with lung cancer, sarcoma, breast cancer, and kidney renal clear cell carcinoma.
The results demonstrated that RNF43 was abnormally expressed in multiple cancers, and RNF43 is a critical prognosis-related factor in several cancers. RNF43 was frequently mutated in several cancers with a high frequency of 4%, and truncating mutation was the most frequent RNF43 mutation type. RNF43 expression was linked to the abundance of several immune cell types, including CD8+ T cells, B cells, and macrophages within the tumor immune microenvironment. Furthermore, RNF43 expression was significantly correlated with the efficacy of anti-PD-1/PD-L1 treatment, and it could predict the sensitivity of various anti-cancer drugs. Finally, IHC explored and validated the different expression levels of RNF43 in different cancers by our clinical samples.
Our results first present the expression pattern and the mutation signature of RNF43, highlighting that RNF43 is an important prognostic biomarker in pan-cancer. Furthermore, RNF43 seems to be a critical modulator in the tumor immune microenvironment and can function as a promising biomarker for predicting the immunotherapeutic efficacy of anti-PD-1/PD-L1 treatment, and drug sensitivity in cancer treatment.
环指蛋白 43（RNF43）是一种 E3 泛素连接酶，在多种癌症中存在同源基因突变。然而，RNF43 在泛癌中的全景图及其对肿瘤免疫表型和免疫治疗疗效的预测价值在很大程度上仍不清楚。我们的研究旨在阐明 RNF43 在预测泛癌中的预后、免疫特征和免疫治疗疗效方面的功能。
通过使用 TCGA 数据库中的 RNA-seq、突变和临床数据，分析 RNF43 在泛癌中的表达水平和预后意义。通过 cBioPortal 数据库展示 RNF43 的遗传改变特征。通过基因集富集分析（GSEA）研究 RNF43 在癌症中调节的潜在生物学功能和信号通路。通过 ESTIMATE 算法、CIBERSORT 算法和 TISIDB 数据库解释 RNF43 表达与免疫细胞浸润和免疫调节剂表达的关系。还研究了 RNF43 与微卫星不稳定性（MSI）和肿瘤突变负担（TMB）之间的相关性。此外，还进一步说明了 RNF43 对免疫治疗疗效和药物敏感性的预测价值。此外，还通过我们的临床队列（包括肺癌、肉瘤、乳腺癌和肾透明细胞癌患者）中的免疫组织化学（IHC）验证了 RNF43 在不同癌症类型中的表达。
结果表明，RNF43 在多种癌症中异常表达，并且 RNF43 是几种癌症中关键的预后相关因素。RNF43 在几种癌症中频繁突变，突变频率为 4%，截断突变是最常见的 RNF43 突变类型。RNF43 表达与肿瘤免疫微环境中几种免疫细胞类型的丰度有关，包括 CD8+T 细胞、B 细胞和巨噬细胞。此外，RNF43 表达与抗 PD-1/PD-L1 治疗的疗效显著相关，并且可以预测各种抗癌药物的敏感性。最后，通过我们的临床样本，免疫组织化学（IHC）探索并验证了 RNF43 在不同癌症中的不同表达水平。
我们的研究结果首次展示了 RNF43 的表达模式和突变特征，强调了 RNF43 是泛癌中重要的预后生物标志物。此外，RNF43 似乎是肿瘤免疫微环境中的关键调节剂，并且可以作为预测抗 PD-1/PD-L1 治疗免疫治疗疗效和癌症治疗药物敏感性的有前途的生物标志物。
